Early blindness leads to structural and functional alteration of the brain, as demonstrated with non-invasive, magnetic resonance imaging (MRI) in human participants. While our preliminary studies replicate the finding that blind participants develop cross-modal responses within their visual cortex (i.e., activation to an auditory stimulus), and have altered cortical structure (i.e., atrophy of the visual cortex white matter and disruption of white matter fiber coherence along the optic radiations), we also find enormous variability across the blind in these measures. This variability is systematic, with a strong correlation across blind subjects within functional measures (i.e., resting blood flow in the occipital lobe covaries with cross-modal responses) and within structural measures (optic radiation disruption correlates with visual cortex atrophy), but a low correlation between structural and functional measures. Different alterations in the visual pathway may therefore depend upon individual clinical features, including age at onset of blindness, severity of blindness, rapidity of visual loss, and development of compensatory abilities (e.g., Braille reading). Understanding these forms of neural plasticity could guide selection of patients most likely to regain useful vision following ophthalmologic treatment, similar to cochlear implant experience for treatment of deafness (HJ Lee et al., 2007). Recent therapeutic developments aim to reverse blindness that is congenital (i.e., targeted gene therapy for Leber's congenital amaurosis 2, LCA; Cideciyan et al., 2008; Maguire et al., 2008) and acquired (i.e., implanted retinal chip for age-related macular degeneration; Thanos et al., 2007). Recently, we have demonstrated that gene therapy in a canine model of LCA leads to increased cortical responses to visual stimuli after treatment (Aguirre et al., 2007). An important translational question is whether specific alterations of brain structure and function can predict restoration of cortical responses and useful vision following ophthalmologic treatment. We will obtain several MRI measures from a diverse population of both completely and incompletely blind individuals. These measures will be both structural (cortical gray matter thickness and white matter volume; white matter coherence by diffusion tensor imaging) and functional (resting cerebral perfusion; cross-modal activation to auditory stimulation; resting-state connectivity; activation to a standardized luminance modulation). We will test the hypothesis that certain alterations cluster together across subjects, and that these alterations are in turn related to individual features of the clinical history of vision loss in each patient. In a population of patients with blindness from RPE65-LCA, we will further determine which of these measures are modified by successful retinal gene therapy to restore vision, and which measures are predictive of functional outcome. The studies will systemically elucidate brain plasticity in vision loss by identifying the determinant factors both of clinical history and from the interplay of regional connectivity and function in the cortex. Our results will have direct translational value for the treatment of blindness, both in the development of compensatory strategies for the blind and for the guidance of clinical trials for ophthalmologic therapy.